The present invention relates to a method of treating damaged mucosal and epithelial tissues. More specifically, this invention relates to a treatment comprising the use of misoprostol, an analog of prostaglandin E.sub.1.
It is estimated that in the United States alone, there are 140,000,000 adults with periodontal disease in varying forms. Periodontal disease starts as inflammatory lesions because of specific bacteria localizing in the area where the gingiva attaches to the tooth. Usually first to occur is a vascular change in the underlying connective tissue. Inflammation in the connective tissue stimulates the following changes in the epithelial lining of the sulcus and in the epithelial attachment:
1. Increased mitotic activity in the basal epithelial layer.
2. Increased producing of keratin with desquamation.
3. Cellular desquamation adjacent to the tooth surface tends to deepen the pocket.
4. Epithelial cells of the basal layer at the bottom of the sulcus and in the area of attachment proliferate into the connective tissue and break up of the gingival fibers begins to occur.
5. The dissolution of the connective tissue results in the formation of an open lesion.
Proliferation of the epithelial attachment along the root and degeneration of the underlying gingival fibers are primary changes in pocket formation. Proliferation of the epithelial attachment is stimulated by local irritation. Inflammation caused by local irritation producers degeneration of the gingival fibers, periodontal ligament and supporting bone, making it easier for the epithelium to move along the root. The coronal portion of the epithelial attachment detaches from the root as the apical portion migrates. With continued inflammation, the gingiva increases in bulk and the crest of the gingival margin extends toward the crown. The epithelium of the lateral wall migrate along the root and separate from it. The epithelium of the lateral wall of the pocket proliferates to form bulbous and coral-like extensions into the inflamed connective tissue. Leukocytes and edema from the inflamed connective tissue infiltrate the epithelium lining the pocket, resulting in varying degrees of degeneration and necrosis.
Periodontal pockets are chronic inflammatory lesions, and as such are constantly undergoing repair. The condition of the soft tissue wall of the periodontal pocket results from a balance between destructive and constructive tissue changes. The destructive changes consist of the fluid and cellular inflammatory exudate and the associated degenerative changes stimulated by local bacterial infiltrate. The constructive changes consist of the formation of connective tissue cells, collagen fibers and blood vessels in an effort to repair tissue damage caused by inflammation. Healing does not go to completion because of the persistence of local irritants (i.e. bacteria). These irritants stimulate fluid and cellular exudate, which in turn causes degeneration of the new tissue elements formed in the repair process.
Edematous and fibrotic pockets represent opposite extremes of the same pathologic process rather than different disease entities. The outer appearance of a periodontal pocket may be misleading because it is not necessarily a true indication of what is taking place throughout the pocket wall. The severest degenerative changes in periodontal pockets occur along the inner aspect. In some cases inflammation and ulceration on the inside of the pocket are walled off by fibrous tissue on the outer aspect. Outwardly the pocket appears pink and fibrotic despite the degeneration taking place within.
Periodontal pockets contain debris which is principally microorganisms and their products (enzymes, endotoxins and other metabolic products), dental plaque, gingival fluid, food remnants, salivary mucin, desquamated epithelial cells and leukocytes. Plaque-covered calculus usually projects from the tooth surface. If a purulent exudate is present, it consists of living, degenerated and necrotic leukocytes (predominantly polymorphonuclear), living cells and dead bacterial cells, serum and a small mount of fibrin.
The root planing both supra and subgingival with curettage is the basic, most commonly employed procedure for elimination of periodontal pockets and the treatment of periodontal disease. It consists of planing to remove calculus, plaque and other deposits, smoothing the root surface to remove necrotic tooth substances and curetting the inner surface of the gingival wall of the periodontal pockets to separate away diseased soil tissue. The purpose is to accomplish elimination of the pocket by reattachment of connective tissue and epithelium to tooth surface obliterating the pocket or environment for microorganisms to grow. The basic healing processes are the same following all forms of periodontal therapy. They consist of the removal of degenerated tissue debris and the replacement of tissues destroyed by disease. Regeneration is the growth and differentiation of new cells and intercellular substances to form new tissues or parts. It consists of fibroplasia, endothelial proliferation, the deposition of interstitial ground substance and collagen, epithelial hyperplasia and the maturation of connective tissue. Bone and cementum are not replaced by existing bone or cementum, but from connective tissue, which is the precursor of both. Undifferentiated connective tissue cells develop into osteoblasts and cementoblasts which form bone and cementum. Regeneration of the periodontum is a continuous physiologic process. Regeneration is a microscopic activity which differs in degrees from clinically radiographically detectable restoration of destroyed periodontal tissues. Regeneration in most instances restores the continuity of the diseased marginal gingiva and reestablishes a normal gingival sulcus at the same level on the root as the base of the pre-existing periodontal pocket. Reattachment is the re-embedding of new periodontal ligament fibers into new cementum and the attachment of gingival epithelium to tooth surface previously denuded by disease.
The majority of periodontal disease is left untreated primarily because prior to the treatment of the present invention people were subjected to surgical procedures which are painful, alters daily routines for months, is quite expensive and frightens patients away from good therapy. The present misoprostol procedure is very conservative with no surgery. It demonstrates regeneration and reattachment with little discomfort to the patient. The cost is about 25% compared to surgical intervention. The procedure has been shown to improve furcation, establishment of and reattachment and regeneration of tissues between roots of multi-rooted molars, which have always been difficult clinically to maintain and usually cause dentition to be hopeless. Its use as a clinical procedure promises to eliminate a multitude of problems associated with dentition loss, i.e. nutrition, comfort, of a population that ages. Today the statistics are that 43% of the adult population are edentulous by age 55. Because of loss of teeth alveolar bone is also lost in time, meaning loss of the ridge that a denture sets on making a very unstable environment. With the conservative treatment of the present invention the number of edentulous people should be reduced over time plus there should also be a reduction of the amount of money spent on periodontal treatment.
The procedure of the present invention is performed under local anesthesia in a dental office. Curettage and root planing procedures are performed first followed by flushing the wound site with a misoprostol solution. For the following week topical application of misoprostol is applied, typically four times per day. After allowing maturity of the tissue and strict plaque control dramatic changes of pocket depths, inflammation with evidence of regeneration and reattachment of the gum tissue is being found. The procedure of the present invention may also be supplemented with anti-infective coverage using metronidazole 250 mg three times per day for the first week while the clinical disease situation was active and acute.
In summary the method of the present invention provides a new treatment that accelerates healing for the patient, reduces trauma from surgeries that no longer need to be performed, and reduces cost to the patient. Also in necessary surgeries such as gingival grafting it accelerates healing of both the donor site and graft site. Using misoprostol with a local anesthetic such as dyclonine makes the surgical procedures almost painless. Also, a reduction of dry sockets after extractions is being found with the present procedure thus almost eliminating them as a problem in the dental office. The advantage for the periodontal patient is that it eliminates much of the surgery if this process is used on early periodontal cases along with good oral hygiene and maintenance care.
The present treatment has also been found effective to treat oral and paraoral ulcers from radiation and/or chemotherapy. The ulcers commonly develop within days after chemotherapy or radiation therapy. These ulcers usually begin as small, painful irregularly shaped lesions usually covered by a delicate gray necrotic membrane and surrounded by inflammatory tissue. If treatment is not instituted, there many times will be beginning proliferation of tissue around the periphery of the lesion on an inflammatory basis.
This type of ulcer is a non-specific ulcer and microscopically shows loss of continuity of surface epithelium with a fibrinous exudate covering the exposed connective tissue. The epithelium bordering the ulcer usually demonstrates proliferative activity. Polymorphonuclear leukocytes infiltrate in the connective tissue, especially beneath the ulcer. Although if chronic these could be replaced by lymphocytes and plasma cells. Also seen is capillary dilation and its proliferation is evident. Fibroblastic activity may also be prominent with macrophages present in limited numbers.
These lesions because of their size and loss of epithelial integrity lend the body to potential secondary infection. Coupled with the secondary infection, which could eminate from the entire alimentary canal or with chemotherapy ulcers could be widely diverse throughout the alimentary canal, would be loss of weight, potential electrolyte imbalance and dehydration. Routine ingestion of food and water becomes a very painful event and if the ulcers proliferate throughout the alimentary canal diarrhea usually is evident with all its complicating factors.
The therapy disclosed herein using misoprostol both as a troche and as a topical application in an oral adhesive dusted on lesions, has shown dramatic results within 3 to 5 days, allowing a patient to resume good nutrition and proper ingestion of fluids. These same results have occurred with the common canker sore that millions of humans have on a routine basis. Non-specific chronic oral ulcerations may also be treated with this regimen. One patient has had chronic aphthous ulcers without relief for years and was even hospitalized because of them. The misoprostol treatment healed the ulcers completely and for over one year there has been no ulcerative recurrence.
Re-epithelialization occurs rapidly with the use of misoprostol when secondary infection is controlled. The usual course of treatment if signs of secondary infections occurs is to dose with antibiotic and/or antifungals, in addition to misoprostol both as a troche and topically applied with an oral adhesive directly to the lesion. When multiple chemotherapy treatments are administered, the misoprostol is prophylactically used prior to outbreaks of lesions to control them and thus minimize outbreaks or in most cases eliminate lesions.
The effect of chemotherapy and radiotherapy are similar. It is based on the ability to non-specifically destroy or retard the division of rapidly proliferating malignant cells with specific drugs or radiation. Normal cells with rapid turnover, such as oral mucosa or the alimentary canal, are also affected and may result in toxicity and complications. Approximately 20% of patients with cancer are treated with chemotherapy at some time during the course of their disease, also there are approximately 250,000 episodes of oral complications each year. This incidence is likely to increase with the use of more potent drugs and multimodality therapy combining radiation and new chemotherapy.
Control of secondary infections using antibiotics and/or antifungal agents in combination with the present misoprostol routine creates re-epithelialization and inflammation reduction within 3 to 5 days, allowing a patient normal nutrition rather than painful stomatitis. The application is directly to the injured ulcerated tissue by troches or dusting with misoprostol preferably 4 to 5 times daily.
Misoprostol is an analog of prostaglandin E.sub.1 and is broken down by most tissues of the body to misoprostol acid, the active metabolyte. Misoprostol has been used in the past on a prescription basis as a gastric mucosa protectant and antiulcer agent. Its primary use is the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcers, and short term treatment of duodenal ulcers. In contrast, the present method demonstrates a stimulation of re-epithelialization of wounds or damaged mucosal tissues and reduced healing times.
Misoprostol may be administered alone or in combination with other pharmaceutically acceptable agents. Dosages of from not less than about 1 .mu.g per day to no more than about 5 mg per day of the individual compounds per se, or in combinations, are generally effective. In this regard, misoprostol is present in a composition in an amount from about 1 .mu.g to about 1 mg per gram of the composition. Various formulations for the compositions are provided herein. Such formulations may include creams, lotions, ointments, and the like. The compositions and/or formulations may also include additional active ingredients if desired, such as local anesthetics.
The method disclosed herein provides a novel method for the treatment or prevention of a variety of damaged mucosal and epithelial tissues. For example, oral, esophageal, nasal, ocular, aural, anal and genital mucosal tissues may all be treated with misoprostol. It will be evident that the method will find ready application for the prevention or treatment of damaged tissues other than those named, for example dermatological tissues, in which faster wound healing is desired. For example, the treatment of the present invention may also find ready application in severe burn and skin regeneration, skin grafts, pressure sores, diabetic ulcers, fissures, post surgery scar reduction, dry socket, ulcerative colitis, rectal and anal fissures. This treatment also improves healing from dermatological surgery, any surgery involving epithelial tissue, extraction sites or periodontal surgeries.
The present method has the distinct unexpected advantage that it will provide a highly effective treatment for damaged tissues, especially mucosal tissues, and all epithelial tissues, and at the same time this compound advantageously will not produce unwanted systemic or local side effects even if the compound is administered continuously on a daily basis, as long as the appropriate compound dosages are used. It, of course, must be understood that the dosage levels will be adjusted dependent on the response of the subject and the degree of damage to the tissues as monitored by methods known to those skilled in the art.